On September 20, 2006 López-Alegría docked with the ISS as Commander of Expedition 14, having taken off from Baikonur, Kazakhstan on September 18, onboard Soyuz TMA-9. On Expedition 14, he performed five spacewalks. On April 21, 2007 he undocked from the ISS and returned to Earth.

López-Alegría holds the all time American record for number of EVAs (10) and total EVA duration (67 hours and 40 minutes). The previous record holder, Jerry L. Ross had a total of 9 EVAs with a duration of 58 hours and 18 minutes. López-Alegría is the second most experienced spacewalker overall, behind Russia's Anatoly Solovyev. On April 2, 2007, López-Alegría set the record for the longest space mission of any American astronaut. When he landed on April 21, his time in space on a single mission was 215 days.[3] (The longest space mission on record is that of Valeriy Polyakov, who spent 437 days aboard the Russian space station Mir in 1994 and 1995.)

At the end of his mission, he commanded the longest flight by a Soyuz spacecraft, making Expedition 14 the longest expedition thus far. López-Alegría broke the record for longest spaceflight by an American astronaut.[4]

López-Alegría retired from NASA on March 12, 2012[5] and served as the President of the Commercial Spaceflight Federation through the end of 2014. López-Alegría is now an independent consultant to traditional and commercial space companies, serves on several advisory boards and committees to public and private organizations, and is engaged in public speaking domestically and internationally. He is based in Washington, DC.